There is increasing evidence that endothelial dysfunction plays a key role in the formation and progression of atherosclerotic plaque as well as in the development of diabetes and diabetic complications. Endothelial dysfunction has recently gained diagnostic, prognostic and therapeutic significance in atherothrombosis and diabetes (Heitzer T, Schlinzig T, Krohn K, Meinertz T, Munzel T. Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation 2001; 104:2673-2678; Schachinger V, Britten M B, Zeiher A M. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 2000; 101:1899-1906; Perticone F, Ceravolo R, Pujia A, Ventura G, Iacopino S, Scozzafava A, Ferraro A, Chello M, Mastroroberto P, Verdecchia P, Schillaci G. Prognostic significance of endothelial dysfunction in hypertensive patients. Circulation 2001; 104:191-196; Suwaidi J A, Hamasaki S, Higano S T, Nishimura R A, Holmes D R, Jr., Lerman A. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation 2000; 101:948-954), de Jager J, Dekker J M, Kooy A, Kostense P J, Nijpels G, Heine R J, Bouter L M et al.: Endothelial dysfunction and low-grade inflammation explain much of the excess cardiovascular mortality in individuals with type 2 diabetes: the Hoorn Study. Arterioscler Thromb Vasc Biol, 2006, 26, 1086-1093).
Endothelial dysfunction is defined as a functional endothelium condition which is characterized by deficiency of vasoprotective factors and enhanced production of pro-coagulative and pro-inflammatory factors (Chlopicki S, Kardiologia po Dyplomie, 2005, Vol. 4 No. 5, 77-88). Clinically, endothelial dysfunction is identified as the impairment of biological activity of NO, which is diagnosed as the impairment of vasodilating NO activity. Monitoring of bioavailability of NO is possible by measurement of NO-dependent vasoconstrictive endothelium function in vivo (Chlopicki S, Kardiologia po Dyplomie, 2005, Vol. 4 No. 5, 75-81). The impairment of NO activity coincides with oxidant stress (Heitzer T, Schlinzig T, Krohn K, Meinertz T, Munzel T. Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation 2001; 104:2673-2678) and impairment of PGI2 synthesis (Kyrle P A, Minar E, Brenner B, Eichler H G, Heistinger M, Marosi L, Lechner K. Thromboxane A2 and prostacyclin generation in the microvasculature of patients with atherosclerosis—effect of low-dose aspirin. Thromb Haemost 1989; 61:374-377), although systemic level of PGI2 may be elevated. Indeed, it has been proposed that increased lipid peroxidation might promote development of atherosclerosis owing to selective impairment of prostacyclin synthesis in endothelial cells and subsequent activation of platelets (Gryglewski R J. Prostacyclin and atherosclerosis. TIPS 1980; 1: 164-168; Gryglewski R J. Prostaglandins, platelets, and atherosclerosis. CRC Crit. Rev Biochem 1980; 7:291-338; Gryglewski R J, Szczeklik A. Prostacyclin and atherosclerosis—experimental and clinical approach. 1983; 213-226). This concept was then supported experimentally. It is apparent now that impairment of PGI2 synthesis in endothelium may lead to the excessive stimulation of TP receptors in endothelium and vascular smooth muscle cells by TXA2, PGH2 or other eicosanoids. Such mechanisms lead to subsequent vasoconstriction, platelet activation, inflammatory response of endothelium as well as endothelial apoptosis (Chlopicki S, Gryglewski R J. Endothelial secretory function and atherothrombosis in “The Eicosanoids”, chapter 23, 267-276. ed. P. Curtis-Prior, John Wiley and Sons, Ltd, 2004). This means that the impairment of PGI2 synthesis in endothelium may trigger or enhance inflammatory and thrombotic processes in vascular wall, which are now considered to be the key elements of atherosclerosis. Endothelial dysfunction plays also the key role in the development of diabetes (de Jager J, Dekker J M, Kooy A, Kostense P J, Nijpels G, Heine R J, Bouter L M et al.: Endothelial dysfunction and low-grade inflammation explain much of the excess cardiovascular mortality in individuals with type 2 diabetes: the Hoorn Study. Arterioscler Thromb Vasc Biol, 2006, 26, 1086-1093.) Therefore, the result of the ability of certain quaternary pyridinium salts to stimulate endothelial PGI2 synthesis can be their potential anti-atherosclerotic and anti-diabetic effects. Similarly, in many other diseases wherein endothelial dysfunction plays a role in pathogenesis, pharmacological enhancement of PGI2 synthesis in endothelium caused by said compounds may bring therapeutic effects. Some of quaternary pyridinium salts can also have therapeutic effects in diseases responding to prostacycline analogs, such as for example liver injuries, pulmonary hypertension, and wound healing.
The use of quaternary pyridinium salts of the formula:
wherein R is NH2, CH3, or N(H)CH2OH group, and X is pharmaceutically acceptable counterion, for the preparation of vasoprotective agent for the treatment or prevention of conditions or diseases associated with dysfunction of vascular endothelium, oxidative stress, and/or insufficient production of endothelial prostacyclin PGI2 is described in WO2005/067927. In particular, anti-atherosclerotic and thrombolytic activity of the compounds of the above formula was shown.
In publications of R. Stadler et al. in. w J. Agric. Food Chem. 2002, 50, 1192-1199 and 1200-1206 products of trigonelline decomposition formed during coffee roasting were reported. Reportedly, the main non-volatile products of trigonelline pyrolysis were 1-methylpyridine and dialkylpyridinium compounds. Potential anticancer activity of alkylpyridinium compounds, especially 1-methylpyridine, was suggested.